Mutant p53 Alleles Can Be Restored to the Wild-Type Conformation

The majority of TP53 mutations are missense mutations that affect the structural properties of the p53 protein and result in a gain-of-function phenotype. As TP53 is the most commonly mutated gene in human tumors, pharmacologic inhibition of mutant p53 activity would likely have clinical benefit. Yu and colleagues ranked the 48,129 chemical compounds used in the National Cancer Institute anticancer drug screen of 60 cancer cell lines for their ability to preferentially inhibit the growth of p53-mutant cells. Among the highest scoring compounds were thiosemicarbazones, metal ion chelators that inhibit DNA synthesis at high concentrations. One compound, NSC319726, was nontoxic to wild-type cells but potently inhibited the growth of cells with an arginine-175 mutation (p53^R175). Interestingly, NSC319726 treatment rendered p53^R175 unrecognizable by a mutant conformation-specific p53 antibody, suggesting that this compound could restore the wild-type protein structure in p53^R175-mutant cells. Indeed, binding by the wild-type–specific p53 antibody increased after NSC319726 treatment and was accompanied by the restoration of p53 promoter binding and transactivation of target genes p21, PUMA, and MDM2. NSC319726 treatment led to widespread apoptosis in p53^R175-knockin mice and significant growth inhibition of p53^R175 tumor xenografts, further indicating that this compound can reactivate normal p53 function. The activity of NSC319726 was dependent on its metal ion chelating and oxidative properties, suggesting that NSC319726 may promote refolding of the p53^R175 mutant by acting as a metallochaperone and regulating cellular redox levels. The identification of thiosemicarbazone compounds as selective inhibitors of p53-mutant cells that restore wild-type p53 structure and function suggests that targeting specific p53 mutant alleles may be a viable therapeutic option.

Yu X, Vazquez A, Levine AJ, Carpizo DR. Allele-specific p53 mutant reactivation. Cancer Cell 2012;21:614–25.

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